rs12592307

Positions:

• chr15-27845027-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000275.3(OCA2):​c.2364G>A​(p.Ser788=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.222 in 1,612,506 control chromosomes in the GnomAD database, including 46,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4160 hom., cov: 32)
  • Exomes 𝑓: 0.22 (42014 hom.)
• Consequence: OCA2 NM_000275.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.606

Genes affected

OCA2 (HGNC:8101): (OCA2 melanosomal transmembrane protein) This gene encodes the human homolog of the mouse p (pink-eyed dilution) gene. The encoded protein is believed to be an integral membrane protein involved in small molecule transport, specifically tyrosine, which is a precursor to melanin synthesis. It is involved in mammalian pigmentation, where it may control skin color variation and act as a determinant of brown or blue eye color. Mutations in this gene result in type 2 oculocutaneous albinism. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 15-27845027-C-T is Benign according to our data. Variant chr15-27845027-C-T is described in ClinVar as [Benign]. Clinvar id is 255730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.606 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.546 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCA2	NM_000275.3	c.2364G>A	p.Ser788=	synonymous_variant	23/24	ENST00000354638.8	NP_000266.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCA2	ENST00000354638.8	c.2364G>A	p.Ser788=	synonymous_variant	23/24	1	NM_000275.3	ENSP00000346659	P1
OCA2	ENST00000353809.9	c.2292G>A	p.Ser764=	synonymous_variant	22/23	1		ENSP00000261276

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31785 AN: 151700 Hom.: 4157 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.563

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.212

GnomAD3 exomes AF: 0.277 AC: 69666 AN: 251336 Hom.: 11865 AF XY: 0.274 AC XY: 37199 AN XY: 135826

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.449

Gnomad ASJ exome AF: 0.320

Gnomad EAS exome AF: 0.564

Gnomad SAS exome AF: 0.309

Gnomad FIN exome AF: 0.240

Gnomad NFE exome AF: 0.198

Gnomad OTH exome AF: 0.261

GnomAD4 exome AF: 0.223 AC: 325647 AN: 1460688 Hom.: 42014 Cov.: 33 AF XY: 0.225 AC XY: 163383 AN XY: 726708

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.435

Gnomad4 ASJ exome AF: 0.324

Gnomad4 EAS exome AF: 0.586

Gnomad4 SAS exome AF: 0.312

Gnomad4 FIN exome AF: 0.232

Gnomad4 NFE exome AF: 0.194

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.209 AC: 31805 AN: 151818 Hom.: 4160 Cov.: 32 AF XY: 0.219 AC XY: 16240 AN XY: 74182

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.332

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.563

Gnomad4 SAS AF: 0.311

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.213

Alfa AF: 0.203 Hom.: 3922

Bravo AF: 0.214

Asia WGS AF: 0.416 AC: 1446 AN: 3478

EpiCase AF: 0.216

EpiControl AF: 0.209

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Tyrosinase-positive oculocutaneous albinism Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.11
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12592307; hg19: chr15-28090173; COSMIC: COSV62341615;